Mismatch repair deficiency is not sufficient to increase tumor immunogenicity

Abstract

DNA mismatch repair deficiency (MMRd) in human cancer is associated with high tumor mutational burden (TMB), frameshift mutation-derived neoantigens, increased T cell infiltration, and remarkable responsiveness to immune checkpoint blockade (ICB) therapy. Nevertheless, about half of MMRd tumors do not respond to ICB for unclear reasons. While tumor cell line transplant models of MMRd have reinforced the importance of TMB in immune response, critical questions remain regarding the role of immunosurveillance in the evolution of MMRd tumors induced in vivo. Here, we developed autochthonous mouse models of lung and colon cancer with highly efficient ablation of MMR genes via in vivo CRISPR/Cas9 targeting. Surprisingly, MMRd in these models did not result in increased immunogenicity or response to ICB. Mechanistically, we showed this lack of immunogenicity to be driven by profound intratumoral heterogeneity (ITH). Studies in animals depleted of T cells further demonstrated that immunosurveillance in MMRd tumors has no impact on TMB but shapes the clonal architecture of neoantigens by exacerbating ITH. These results provide important context for understanding immune evasion in cancers with high TMB and have major implications for therapies aimed at increasing TMB.

Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer

“…Additionally, the complex TME in GEMMs, a pertinent reflection of the patient tumor, makes it difficult to say with certainty that the impact of glutaminase inhibition in the CD8 T cells alone was responsible for their impeded function, and not a result of the cross talk within cells of the TME. Finally, given that KEAP1 and STK11 mutant lung adenocarcinoma are generally associated with cigarette smoke and high tumor mutational burden (TMB) (Ricciuti et al, 2022;Skoulidis et al, 2015), it will be important to validate these findings in murine models engineered to exhibit a higher TMB and/or neoantigens (Fitzgerald et al, 2021;Westcott et al, 2021). Despite this, our findings suggest that glutaminase function must be unimpeded in CD8 T cells to ensure that they have the ability to reach their full cytotoxic potential.…”

Mutation Rate Evolution Drives Immune Escape In Mismatch Repair-Deficient Cancer

“…We then examined subclonal neoantigen complexity. Recent data from preclinical models 25 as well as patient cohorts 26 suggest that an increased number of subclonal neoantigens can drive early immune exhaustion and lack of checkpoint inhibitor treatment response. We find that subclones carrying either MSH6 F1088fs or MSH3 K383fs indels show a greater proportion of subclonal predicted neoantigens ( Fig.…”

“…A mutator strategy exacerbates intratumour heterogeneity and increases subclonal neo-antigen burden. Recent preclinical studies indicate that increased subclonal complexity and subclonal neoantigen burdens blunt immune responses to checkpoint inhibitors in MMRd animal models due to immune exhaustion 25 . In line with this, we have recently found that low neoantigen clonality predicts lack of response to checkpoint inhibitors in MMRd patients 26 .…”

Therapy sculpts the complex interplay between cancer and the immune system during tumour evolution

“…Tumours are often composed of a myriad of distinct cancer subclones, which may harbour distinct sets of mutations affecting sensitivity or resistance to therapy. Emerging work suggests that clonal neoantigens may elicit a more sustained and effective immune response [97]. Less heterogeneous tumours derived by single-cell cloning of cells from a UVB radiation-exposed melanoma cell line, which had a lower number of tumour subclones than their parental cells, were shown to exhibit increased immunogenicity and slower tumour growth [98].…”